Leukemias are a heterogeneous group of cancers of the blood forming organs characterized by production of abnormal leukocytes, their release to circulation and infiltration of organs. The U.S. National Cancer Institute estimates that there were 43,050 new cases in 2010 and 21,840 leukemia-related deaths. Where leukemias can occur at any age, about 90% of cases are diagnosed in adults. By far, the cause of leukemia in the majority of cases is unknown (Itakura H, Coutre S E: Acute lymphoblastic leukemia in adults. In: Greer J P, et al., editors. Leukemia in adults. Philadelphia: Lippincott Williams and Wilkins. 2009. p. 1820; Faderel S, et al., Acute lymphoblastic leukemia. In: Hong W K, et al., editors. Holland-Frei cancer medicine. Eighth Edition, Shelton, Conn.: People's Medical Publishing House, 2010. p. 1591; MacArthur A C, et al., Risk of Childhood Leukemia Associated with Vaccination, Infection, and Medication Use in Childhood. Am J Epidemiol. 2008; 167 (5):598-606). Some of the suggested causes include natural and artificial ionizing radiation (Maloney W. Leukemia in survivors of atomic bombing. N Eng J. Med. 1955; 253:88; Preston D, Kusumi S, Tomonaga M, et al. Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and myeloma, 1950-1987. Radiat Res. 1994; 137:S68-S97; Little M P, et al., The statistical power of epidemiological studies analyzing the relationship between exposure to ionizing radiation and cancer, with special reference to childhood leukemia and natural background radiation. Radiat Res. 2010; 174 (3):387-402; Davies A, Modan B, Djaldetti M, et al. Epidemiological observations on leukemia in Israel. Arch Intern Med. 1961; 108 (1): 86-90), viruses such as Epstein-Barr Virus (Tokunaga M, et al., Epstein-Barr virus in adult T-cell leukemia/lymphoma. Am J Pathol. 1993; 143 (5): 1263-1268), Human T-lymphotropic virus (HTLV-1) (Phillips A A, et al., A critical analysis of prognostic factors in North American patients with human T-cell lymphotropic virus type-1-associated adult T-cell leukemia/lymphoma: a multicenter clinicopathologic experience and new prognostic score. Cancer. 2010; 116 (14):3438-3446; Jeang K T. HTLV-1 and adult T-cell leukemia: insights into viral transformation of cells 30 years after virus discovery. J Formos Med. Assoc. 2010; 109 (10): 688-93), infections (Greaves M F, Alexander F E. An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia. 1993; 7:349-360; Smith M A, et al., Investigation of leukemia cells from children with common acute lymphoblastic leukemia for genomic sequences of the primate polyomaviruses, JC virus, BK virus and simian virus 40. Med Pediatr Oncol. 1999; 33:441-443; Smith M A, et al., Evidence that childhood acute lymphoblastic leukemia is associated with an infectious agent linked to hygiene conditions. Cancer Causes Control. 1998; 9:285-298), some chemicals such as benzene and alkylating chemotherapy agents (Wen W Q, et al., Paternal military service and risk for childhood leukemia in offspring. Am J Epidemiol. 2000; 151:231-240; Momota H, et al., Acute lymphoblastic leukemia after temozolomide treatment for anaplastic astrocytoma in a child with a germline TP53 mutation. Pediatr Blood Cancer. 2010; 55 (3):577-9; Borgmann A, et al., Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. ALL-REZ BFM Study Group. Eur J Cancer. 2008; 44 (2):257-68), familial predisposition (Karakas Z, Tugcu D, Unuvar A, Atay D, Akcay A, Gedik H, Kayserili H, Dogan O, Anak S, Devecioglu O. Li-Fraumeni syndrome in a Turkish family. Pediatr Hematol Oncol. 2010; (4):197-305; Buffer P A, et al., Environmental and genetic risk factors for childhood leukemia: Appraising the evidence. Cancer Investigation. 2005; 23 (1): 60-75), medications (Tebbi C K, et al., Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007; 25 (5):493-500), genetic factors, chromosomal and metabolic abnormalities (Fong C T, Brodeur G M. Down's syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis. Cancer Genet Cytogenet. 1987; 28 (1): 55-76; Chao M M, et al., T-cell acute lymphoblastic leukemia in association with Borjeson-Forssman-Lehman syndrome due to a mutation in PHF6. Pediatr Blood Cancer. 2010; 55 (4): 722-4; Kato K, et al., Late recurrence of precursor B-cell acute lymphoblastic leukemia 9 years and 7 months after allogenic hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2010; 32 (7):e290-3; Smith M T, et al., Low NAD(P)H: quinine oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood. 2001; 97:1422-1426; Hengstler J G, et al., Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. Recent Results Cancer Res. 1998; 154:47-85; Schenk T M, et al., Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia. Leukemia. 1998; 12:666-674; Felix C A, et al, Immunoglobulin and T cell receptor gene configuration in acute lymphoblastic leukemia of infancy. Blood. 1987; 70:536-541), immune disorders (Vajdic C M, et al., Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood. 2010; 116 (8):1228-34), and environmental issues (Magnani C, et al., Parental occupation and other environmental factors in the etiology of leukemias and non-Hodgkin's lymphomas in childhood: a case-control study. Tumori. 1990; 76 (5):413-9; Non-Ionizing Radiation, Part 1: Static and Extremely Low-Frequency (ELF) Electric and Magnetic Fields (IARC Monographs on the Evaluation of the Carcinogenic Risks). Geneva: World Health Organization. pp. 332-333, 338, 2002; Kroll M E, et al., Childhood cancer and magnetic fields from high-voltage lines in England and Wales: a case-control study. Br J Cancer. 2010; 103 (7):1122-7; Little, M P, et al., The statistical power of epidemiological studies analyzing the relationship between exposure to ionizing radiation and cancer, with special reference to childhood leukemia and natural background radiation. Radiat Res 2010; 174 (3):387-402). None of the above factors can be consistently applied to a majority of cases, nor have they been definitely proven to predictably induce leukemia in all exposed individuals.
Leukemias may be subdivided into groups, including acute and chronic leukemia. In acute leukemia, there is a rapid increase in immature white blood cells (leukocytes) formed in the bone marrow and a reduction in production of normal blood cells. Acute leukemias include acute lymphoblastic leukemias (ALL) and acute myelogenous leukemias (AML). Chronic leukemias include chronic lymphocytic and myelogenous leukemia (CLL and CML). Due to the rapid progression and accumulation of the malignant cells in acute leukemias, immediate treatment is required.
Acute leukemias are the most common forms of cancer in children. Acute lymphoblastic leukemia (ALL) and diffuse lymphomas constitute a significant portion of cancers in childhood. ALL is the most frequent leukemia in the pediatric population (Pui C H. Acute lymphoblastic leukemia in children. Curr opin oncol. 2000; 12:3-12) accounting for a quarter of all childhood cancers and approximately 75% of all leukemias in children, with peak incidence of two to five years of age (Pui C H. Acute lymphoblastic leukemia in children. Curr opin oncol. 2000; 12:3-12; Miller R. Acute lymphocytic leukemia. In: C K Tebbi, editor. Major Topics in Pediatric and Adolescent Oncology. Boston: GK Hall Medical Publishers; 1982. p. 3-43). To date, despite numerous attempts, the cause of leukemia in childhood remains unknown, except for isolated cases. As outlined above, various etiologies such as viral infections, chemical exposure, medications, ionizing radiation chromosomal abnormalities/genetic factors, immune deficiency, environmental issues, etc. have been proposed, but none has been definitively proven or can be consistently applied to the majority of cases. The International Agency for Research on Cancer performed a retrospective study on leukemia occurrence in association with electrical power lines and found limited evidence that high levels of extremely low frequency magnetic fields may result in a twofold increased risk of some childhood leukemias, but this finding was later refuted (Non-Ionizing Radiation, Part 1: Static and Extremely Low-Frequency (ELF) Electric and Magnetic Fields (IARC Monographs on the Evaluation of the Carcinogenic Risks). Geneva: World Health Organization. pp. 332-333, 338, 2002; Kroll M E, et al., Childhood cancer and magnetic fields from high-voltage lines in England and Wales: a case-control study. Br J Cancer. 2010; 103 (7):1122-7; Little M P, et al., The statistical power of epidemiological studies analyzing the relationship between exposure to ionizing radiation and cancer, with special reference to childhood leukemia and natural background radiation. Radiat Res 2010; 174 (3):387-402).
Diagnosis of leukemia is usually based on complete blood counts, bone marrow examination by light microscopy, flow cytometric determination of cell surface phenotypes and other studies. In lymphomas, a lymph node biopsy can be performed for a diagnosis using pathology and flow cytometry, as well as other tests. Usually in leukemias and lymphomas, a cytogenetic evaluation is also performed and may have prognostic value. In acute leukemias and diffuse lymphomas, a spinal tap is required to rule out central nervous system involvement.
Most forms of acute lymphoblastic leukemias are treated with a multi-drug chemotherapy regimen, such as prednisone, L-asparaginase, vincristine, daunorubicin, antimetabolites, with or without radiation therapy (radiotherapy) to the central nervous system (Pui C H. Acute lymphoblastic leukemia in children. Curr opin oncol. 2000; 12:3-12). In some cases, during remission or after relapse, bone marrow transplantation may be required. The general goal of treatment is to obtain normal bone marrow production, called remission, and eliminate the systemic infiltration of organs by leukemic cells.
To date, the means of diagnosing leukemia has required highly skilled individuals and equipment analyzing various parameters, including bone marrow examinations, flow cytometry, and cytogenetics. These tests possess an inherent amount of uncertainty based on the technical expertise of the diagnosing physicians and technical staff and also require a significant amount of time to perform. No definitive laboratory test to predict predisposition to leukemia prior to its occurrence is currently available. Furthermore, there are no systemic screening tools to screen populations including infants and children. Additionally, there are no known methods for the prevention of leukemias and lymphomas in susceptible individuals. Accordingly, what is needed is a quick and reliable method to determine predisposition and diagnose leukemias and lymphomas, and screen for vaccines and compounds to prevent leukemia.